New gene therapy approach shows signs of preventing vision loss from glaucoma

Mount Sinai aerial shot
Mount Sinai researchers developed a gene therapy approach to glaucoma and other retinal diseases and is in discussions with companies looking to move the development into the clinic. (Mount Sinai Health System)

Glaucoma can cause blindness and has no cure, as current therapies only slow vision loss by decreasing elevated eye pressure. Mount Sinai researchers have developed a one-time gene therapy that they hope will prevent vision loss induced by glaucoma and other conditions that cause retinal degeneration.

The researchers found that by reactivating an enzyme called CaMKII in retinal ganglion cells, which are responsible for sending images to the brain to process visual cues, they were able to prevent vision loss in mouse models of glaucoma. The results of the new study, published Thursday in the online version of the journal Cell, have led to commercial interest that could one day translate into new treatments.

The team started by testing CaMKII (calcium/calmodulin-dependent protein kinase II pathway) in a wide range of eye-disease models. They discovered that it is critical to the survival of retinal ganglion cells, making it a “desirable therapeutic target” for preserving vision, said senior author Bo Chen, Ph.D., director of the Ocular Stem Cell Program at Mount Sinai’s Icahn School of Medicine, in a statement.

The researchers then used an adeno-associated viral vector to introduce an over-active version of CaMKII into the retinal ganglion cells of the mouse models just before they became damaged.

In the gene therapy-treated mice, 77% of the retinal ganglion cells survived 12 months after they were damaged, compared to 8% in the control group. The same results occurred six months after optic nerve crush, which leads to slower degeneration, versus 7% in the control mice. 

"The fact that manipulation of CaMKII would involve a one-time transfer of a single-gene adds to its vast potential to treat serious retinal conditions in humans," Chen said. "The next step is testing this in larger animal models, which may pave the way for starting clinical trials."

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CaMKII has been studied in gene therapy research for other indications, as well. In July 2019, researchers at Boston Children’s Hospital said they created a gene therapy that targeted irregularities in CaMKII to treat cardiac diseases marked by irregular heartbeats. 

In March, scientists at the University of Cambridge said they developed a gene therapy expressing two therapeutic proteins that showed promise in mouse models of glaucoma and of misfolded tau protein, which is linked to Alzheimer’s and dementia. A modified version of that therapy is now being developed by Astellas.

There have been some disappointments in bringing forward gene therapies for eye diseases, however. Biogen said in June that its candidate for choroideremia, a rare genetic retinal disease that causes progressive vision loss and ultimately blindness, had failed a late-stage clinical trial.

Roche also struggled to advance a gene therapy for choroideremia. Ten days after Biogen’s blunder, Roche said it was walking away from a deal with 4D Molecular Therapeutics on a sponsored trial. The small biotech said it will move forward with developing the therapy after it regains the full rights in September.

The Mount Sinai team is now filing patent applications for its gene therapy and is in active discussions with multiple companies to move the treatment into the clinic, Mount Sinai said.